Hypertriglyceridemia is being increasingly recognized as an independent risk factor for cardiovascular disease. Although fibrates are commonly used for treatment of hypertriglyceridemia, the therapeutic response varies considerably due to environmental and genetic factors. We propose to test the hypothesis that differences in therapeutic effects of fibrates are related to variations in networks of genes regulating lipoprotein metabolism. An efficient approach for identifying and categorizing major gene variants is based on determination of sequence haplotypes. We plan to study only Hispanics to provide a homogenous population for this genetic study. Furthermore, Hispanics are the fastest growing ethnic group in the U.S. and have a higher prevalence of hypertriglyceridemia than other ethnic groups. We will measure plasma triglycerides (TG), other lipids and lipoproteins, and lipoprotein particle size before and after treatment with fenofibrate in 800 Hispanic individuals with hypertriglyceridemia. We will reconstruct the haplotypes of 16 candidate genes known to regulate TG metabolism and mediate the effect of fibrates. The associations between phenotypes and major haplotypes will be analyzed in a two stage design, with the first half of the sample serving a hypothesis-generating function. Those candidate gene haplotypes that are found to be associated with quantitative traits and drug responses in the first half of the sample will then be tested for confirmation in the second half. In addition, data from the full cohort will be analyzed to identify additional pharmacogenetic associations that may require greater statistical power. Finally, direct fine mapping will be performed in the four most promising genes to identify the responsible variations. Successful completion of this project will provide information on genetic variants associated with phenotypic changes induced by fibrates allowing a better understanding of the mechanism of action of this group of drugs. More importantly, this project will provide lacking information about the function of genes involved in regulating TG and lipoprotein metabolism. This will allow new therapeutic approaches to hypertriglyceridemia to be developed and lead to new genetic markers that allow tailoring treatment to individual patients. The study will target Hispanics who have a high prevalence of hypertriglyceridemia and could provide better understanding of the genetic basis of this condition in this rapidly growing minority group. [unreadable] [unreadable]